Targeting sulfation-dependent mechanoreciprocity between matrix and osteoblasts to mitigate bone loss
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ABSTRACT:
PROVIDER: PRJNA974428 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR24660377_1.fastq.gz | Fastqsanger.gz | |||
| SRR24660377_2.fastq.gz | Fastqsanger.gz | |||
| SRR24660378_1.fastq.gz | Fastqsanger.gz | |||
| SRR24660378_2.fastq.gz | Fastqsanger.gz | |||
| SRR24660379_1.fastq.gz | Fastqsanger.gz |
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Project description:Sulfation is a widespread modification for biomolecules so far poorly explored. Through cross phenotype meta-analysis for human bone mineral density up to 426824 participants and phenotypic characterization of multiple mutant mouse lines, we identified a causative role of the sulfate transporter SLC26A2 deficiency in osteoporosis. Ablation of SLC26A2 in osteoblasts caused severe bone loss and accumulation of immature bone cells and elicited a peculiar pericellular matrix (PCM) outcome, undersulfation coupled with decreased stiffness. Consequently, such altered chemophysical properties of PCM disrupted focal adhesion formation of osteoblasts. Based on bulk RNA sequencing and functional assays, we held a mechano-reciprocal tandem inhibition of FAK and YAP/TAZ responsible for impinged osteoblast maturation by SLC26A2 deficiency, where sulfation and stiffness of PCM were compromised by defective sulfate uptake and thus to exert an outside-in impediment to FAK-dependent YAP/TAZ activity required for osteoblast maturation. Moreover, pharmacological abrogation of the Hippo kinases and forced wheel-running concordantly ameliorated SLC26A2-deficient osteoporosis via enforcement of YAP/TAZ activity. Intriguingly, “guilt by association” analysis of single-cell sequencing data suggested coordination between sulfate metabolism, focal adhesion and YAP/TAZ activity during osteoblast-to-osteocyte transition. As seen in ovariectomized mice and patients with osteoporosis, tandem inhibition of FAK and YAP/TAZ apparently engaged in pathology of broader types of osteoporosis beyond SLC26A2 context. Collectively, these data unveil an unanticipated role of sulfation in developmental mechanoreciprocity between matrix and osteoblasts, which could be leveraged to prevent bone loss.
2023-05-25 | GSE232923 | GEO
Project description:Tumor extracellular matrices (ECM) exhibit aberrant changes in composition and mechanics compared to normal tissues. Proteoglycans (PG) are vital regulators of cellular signaling in the ECM with ability to modulate receptor tyrosine kinase (RTK) activation via their sulfated glycosaminoglycan (sGAG) side chains. However, their role on tumor cell behavior is controversial. Here, we demonstrate that PGs are heavily expressed in lung adenocarcinoma patients in correlation with invasive phenotype and poor prognosis. We developed an engineered human lung tumor model which recapitulate the increase of sGAGs in tumors in an organotypic matrix with independent control of stiffness, viscoelasticity, ligand density and porosity. Our model reveals that increased sulfation stimulates extensive proliferation, epithelial-mesenchymal transition and stemness in cancer cells. We identified the FAK-PI3K-Akt signaling axis as a mediator of sulfation-induced molecular changes in cells upon activation of a distinct set of RTKs within tumor-mimetic hydrogels. We employed an integrative omics and network modeling approach to uncover the transcriptomic landscape of tumor cells in response to sulfation which demonstrated resemblance to PG-rich patient tumors.
2024-07-29 | GSE273281 | GEO
Project description:Matrix mineralization controls gene expression in osteoblasts
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Project description:Osteoblasts are adherent cells. Under physiological conditions they attach to mineralized and non-mineralized osseous surfaces. However, how exactly osteoblasts respond to these different osseous surfaces is largely unknown. Our hypothesis was that the state of matrix mineralization provides a functional signal to osteoblasts. To assess the osteoblast response to mineralized compared to demineralized osseous surfaces, we assessed the transcriptom.
2018-09-30 | GSE114237 | GEO
Project description:Extracellular matrix sulfation in the tumor microenvironment stimulates cancer stemness and invasiveness
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Project description:Embryonic stem (ES) cells continuously decide whether to maintain pluripotency or differentiate. While exogenous LIF and BMP4 perpetuate a pluripotent state, less is known about factors initiating differentiation. We show that heparan sulfate (HS) proteoglycans are critical co-receptors for signals inducing ES cell differentiation. Genetic targeting of NDST1 and 2, two enzymes required for N-sulfation of proteoglycans, blocked differentiation. This phenotype was rescued by HS presented in trans or by soluble heparin. NaClO3-, which reduces sulfation of proteoglycans, potently blocked differentiation of wild type cells. Mechanistically, N-sulfation was identified to be critical for functional autocrine FGF4 signalling. Micro array analysis identified the pluripotency maintaining transcription factors Nanog, KLF2/4/8, Tbx3 and Tcf3 to be negatively regulated, whereas markers of differentiation such as Gbx2, Dnmt3b, FGF5 and Brachyury were induced by sulfation-dependent-FGFR signalling. We show that several of these genes are heterogeneously expressed in ES cells and targeting of heparan sulfation or FGFR-signalling facilitated a homogenous Nanog/KLF4/Tbx3 positive ES cell state. This finding suggests that the recently discovered heterogeneous state of ES cells is regulated by HS-dependent FGFR signalling. Similarly, culturing blastocysts with NaClO3- eliminated GATA6 positive primitive endoderm progenitors generating a homogenous Nanog positive inner cell mass. Functionally, reduction of sulfation robustly improved de novo ES cell derivation efficiency. We conclude that N-sulfated HS is required for FGF4 signalling to maintain ES cells primed for differentiation in a heterogeneous state. Inhibiting this pathway facilitates a more naïve ground state. Four groups with three biological replicates and a technical duplicate in each
2010-04-09 | E-GEOD-15974 | biostudies-arrayexpress
Project description:Embryonic stem (ES) cells continuously decide whether to maintain pluripotency or differentiate. While exogenous LIF and BMP4 perpetuate a pluripotent state, less is known about factors initiating differentiation. We show that heparan sulfate (HS) proteoglycans are critical co-receptors for signals inducing ES cell differentiation. Genetic targeting of NDST1 and 2, two enzymes required for N-sulfation of proteoglycans, blocked differentiation. This phenotype was rescued by HS presented in trans or by soluble heparin. NaClO3-, which reduces sulfation of proteoglycans, potently blocked differentiation of wild type cells. Mechanistically, N-sulfation was identified to be critical for functional autocrine FGF4 signalling. Micro array analysis identified the pluripotency maintaining transcription factors Nanog, KLF2/4/8, Tbx3 and Tcf3 to be negatively regulated, whereas markers of differentiation such as Gbx2, Dnmt3b, FGF5 and Brachyury were induced by sulfation-dependent-FGFR signalling. We show that several of these genes are heterogeneously expressed in ES cells and targeting of heparan sulfation or FGFR-signalling facilitated a homogenous Nanog/KLF4/Tbx3 positive ES cell state. This finding suggests that the recently discovered heterogeneous state of ES cells is regulated by HS-dependent FGFR signalling. Similarly, culturing blastocysts with NaClO3- eliminated GATA6 positive primitive endoderm progenitors generating a homogenous Nanog positive inner cell mass. Functionally, reduction of sulfation robustly improved de novo ES cell derivation efficiency. We conclude that N-sulfated HS is required for FGF4 signalling to maintain ES cells primed for differentiation in a heterogeneous state. Inhibiting this pathway facilitates a more naïve ground state.
2009-11-13 | GSE15974 | GEO
Project description:The incidence and prevalence of inflammatory bowel disease (IBD) is gradually increasing. A high-fat diet (HFD) is known to disrupt intestinal homeostasis and aggravate IBD, yet the underlying mechanisms remain largely undefined. Here, a positive correlation between dietary fat intake and disease severity in both IBD patients and HFD-fed mice is observed. HFD induces a significant decrease in indole-3-acetic acid (IAA) and lead to intestinal barrier damage. Furthermore, IAA supplementation enhances the intestinal mucin sulfation and effectively alleviates colitis. Mechanistically, IAA upregulates key molecules involved in mucin sulfation, including Papss2 and Slc35b3, the synthesis enzyme and the transferase of 3'-phosphoadenosine-5'-phosphosulfate (PAPS), via the Aryl Hydrocarbon Receptor (AHR). More importantly, AHR can directly bind to the transcription start site of Papss2. Oral administration of Lactobacillus reuteri, which can produce IAA, contributes to protecting against colitis and promoting mucin sulfation, while the modified L. reuteri strain lacking the iaaM gene (LactobacillusΔiaaM) and the ability to produce IAA fails to exhibit such effects. Overall, IAA enhances intestinal mucin sulfation through AHR, contributing to the protection of intestinal homeostasis.
2024-05-26 | GSE249996 | GEO
Project description:Background: Ectopic vascular calcifications represent a major clinical problem associated with cardiovascular disease and mortality. However, the mechanisms underlying pathological vascular calcifications are largely unknown hampering the development of therapies to tackle this life threatening medical condition. Results: In order to gain insight into the genes and mechanisms driving this pathological calcification process we analyzed the transcriptional profile of calcifying vascular smooth muscle cells (C-VSMCs). These profiles were compared to differentiating osteoblasts, cells that constitute their physiological calcification counterparts in the body. Overall the transcriptional program of C-VSMC and osteoblasts did not overlap. Several genes, some of them relevant for bone formation, were distinctly modulated by C-VSMCs which did not necessarily lose their smooth muscle cell markers while calcifying. Bioinformatics gene clustering and correlation analysis disclosed limited bone-related mechanisms being shared by two cell types. Extracellular matrix (ECM) and biomineralization genes represented common denominators between pathological vascular and physiological bone calcifications. These genes constitute the strongest link between these cells and represent potential drivers for their shared end-point phenotype. Conclusions: the analyses support the hypothesis that VSMC trans-differentiate into C-VSMCs keeping their own identity while using mechanisms that osteoblasts use to mineralize. The data provide novel insights into groups of genes and biological processes shared in MSC and VSMC osteogenic differentiation. The distinct gene regulation between C-VSMC and osteoblasts might hold clues to find cell-specific pathway modulations, opening the possibility to tackle undesired vascular calcifications without disturbing physiologic bone formation and vice versa. Total RNA obtained from hMSC and hVSMC cultured in osteogenic differentiation medium supplemented with 1.8 mM Ca2+ for 0, 2, 8, 12 or 25 days respectively. For each timepoint 3 replicates were used, with exception for day 0 where 4 replicates were collected.
2014-10-10 | E-GEOD-37558 | biostudies-arrayexpress
Project description:Background & Aims: Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer deaths in the United States. Tyrosine sulfation, catalyzed by the tyrosylprotein sulfotransferase 2 (TPST2), is a post-translational modification essential for protein-protein interactions and cellular functions. SLC35B2 is a key transporter that transports the universal sulfate donor 3’-phosphoadenosine 5’-phosphosulfate (PAPS) into the Golgi apparatus where the protein sulfation occurs. The goal of this study is to determine whether and how SLC35B2-TPST2 axis of tyrosine sulfation plays a role in PDAC. Methods: Gene expression was analyzed in PDAC patients and mice. Human PDAC MIA PaCa-2 and PANC-1 cells were used for in vitro studies. TPST2 deficient MIA PaCa-2 cells were generated to assess xenograft tumor growth in vivo. Mouse PDAC cells derived from the KrasLSL-G12D/+;Tp53L/+;Pdx1-Cre (KPC) mice were used to generate Tpst2 KO KPC cells to evaluate tumor growth and metastasis in vivo. Results: High expressions of SLC35B2 and TPST2 were correlated with poor PDAC patient survival. Knockdown of SLC35B2 or TPST2, or pharmacological inhibition of sulfation inhibited PDAC cell proliferation and migration in vitro. TPST2 deficient MIA PaCa-2 cells exhibited inhibited xenograft tumor growth. Orthotopic inoculation of Tpst2 KO KPC cells in mice showed inhibition of primary tumor growth, local invasion, and metastasis. Mechanistically, the integrin ITGB4 was found to be a novel substrate of TPST2. Inhibition of sulfation destabilizes ITGB4 protein, which may have accounted for the suppression of metastasis. Conclusions: Targeting the SLC35B2-TPST2 axis of tyrosine sulfation may represent a novel approach for therapeutic intervention of PDAC.
2023-10-08 | GSE215104 | GEO